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PubMed1993

Cranial neural crest cells synthesize and secrete a latent form of transforming growth factor beta that can be activated by neural crest cell proteolysis.

Transforming growth factor beta (TGF-beta) is an important regulator of cell growth and differentiation. TGF-beta is usually secreted in a latent form (i.e., not biologically active) that can be activated by limited exposure to low pH or specific proteolytic cleavage. In this study, we (1) assayed cranial neural crest (NC) cell-conditioned medium for the presence of active and latent TGF-beta, (2) determined whether TGF-beta was activated by NC-generated plasmin, and (3) examined whether active TGF-beta 1 regulates NC cell plasminogen activator activity. Results show that under serum-free conditions, essentially all of the TGF-beta secreted by NC cells is in a latent form. However, 24 hr after adding plasminogen to the cultures, active TGF-beta was detectable. Treatment of NC cells with active TGF-beta 1 significantly decreased NC cell plasminogen activator activity. These data suggest that NC cells secrete a latent form of TGF-beta that can be activated under conditions favoring the generation of local proteolytic activity and that levels of plasminogen activator activity may be autoregulated via an autocrine effect of this growth factor.

Animals↗
PubMed2002

Genomic analysis of neural crest induction.

The vertebrate neural crest is a migratory stem cell population that arises within the central nervous system. Here, we combine embryological techniques with array technology to describe 83 genes that provide the first gene expression profile of a newly induced neural crest cell. This profile contains numerous novel markers of neural crest precursors and reveals previously unrecognized similarities between neural crest cells and endothelial cells, another migratory cell population. We have performed a secondary screen using in situ hybridization that allows us to extract temporal information and reconstruct the progression of neural crest gene expression as these cells become different from their neighbors and migrate. Our results reveal a sequential 'migration activation' process that reflects stages in the transition to a migratory neural crest cell and suggests that migratory potential is established in a pool of cells from which a subset are activated to migrate.

Animals↗
PubMed2001

FGF2 promotes skeletogenic differentiation of cranial neural crest cells.

The cranial neural crest gives rise to most of the skeletal tissues of the skull. Matrix-mediated tissue interactions have been implicated in the skeletogenic differentiation of crest cells, but little is known of the role that growth factors might play in this process. The discovery that mutations in fibroblast growth factor receptors (FGFRs) cause the major craniosynostosis syndromes implicates FGF-mediated signalling in the skeletogenic differentiation of the cranial neural crest. We now show that, in vitro, mesencephalic neural crest cells respond to exogenous FGF2 in a dose-dependent manner, with 0.1 and 1 ng/ml causing enhanced proliferation, and 10 ng/ml inducing cartilage differentiation. In longer-term cultures, both endochondral and membrane bone are formed. FGFR1, FGFR2 and FGFR3 are all detectable by immunohistochemistry in the mesencephalic region, with particularly intense expression at the apices of the neural folds from which the neural crest arises. FGFRs are also expressed by subpopulations of neural crest cells in culture. Collectively, these findings suggest that FGFs are involved in the skeletogenic differentiation of the cranial neural crest.

Animals↗
PubMed1997

The origins of the neural crest. Part I: embryonic induction.

Neural crest cells form at the border between the neural plate and the epidermis. The tissue interactions that underlie neural crest cell induction have been investigated primarily by heterotopic grafting experiments in vivo and by conjugating different tissues in vitro. Three models have been proposed to explain the induction of neural crest cells at the neural plate border, i.e. (1) the influence of signals from the mesoderm, (2) changes in ectodermal competence and (3) local interactions between neural and non-neural ectoderm. The weight of the evidence supports the last model, although there are data that suggest a role for signals from the mesoderm. FGFs seem to be necessary but not sufficient for neural crest cell induction. BMP-4 is sufficient to induce neural crest cells from chick neural explants in vitro and intermediate levels of BMP-4-signalling induce neural crest cell markers in Xenopus animal cap assays. These data suggest a gradient model in which neural crest cells are induced by a particular range of BMP-4 activity, although a single-signal model may be too simplistic. Neural crest cell induction may be an ongoing process, in which an initial induction at the neural plate border is followed by further induction within the dorsal neural tube.

Animals↗
PubMed1998

Effects of Shh and Noggin on neural crest formation demonstrate that BMP is required in the neural tube but not ectoderm.

To define the timing of neural crest formation, we challenged the fate of presumptive neural crest cells by grafting notochords, Sonic Hedgehog- (Shh) or Noggin-secreting cells at different stages of neurulation in chick embryos. Notochords or Shh-secreting cells are able to prevent neural crest formation at open neural plate levels, as assayed by DiI-labeling and expression of the transcription factor, Slug, suggesting that neural crest cells are not committed to their fate at this time. In contrast, the BMP signaling antagonist, Noggin, does not repress neural crest formation at the open neural plate stage, but does so if injected into the lumen of the closing neural tube. The period of Noggin sensitivity corresponds to the time when BMPs are expressed in the dorsal neural tube but are down-regulated in the non-neural ectoderm. To confirm the timing of neural crest formation, Shh or Noggin were added to neural folds at defined times in culture. Shh inhibits neural crest production at early stages (0-5 hours in culture), whereas Noggin exerts an effect on neural crest production only later (5-10 hours in culture). Our results suggest three phases of neurulation that relate to neural crest formation: (1) an initial BMP-independent phase that can be prevented by Shh-mediated signals from the notochord; (2) an intermediate BMP-dependent phase around the time of neural tube closure, when BMP-4 is expressed in the dorsal neural tube; and (3) a later pre-migratory phase which is refractory to exogenous Shh and Noggin.

Animals↗
PubMed1990

The sympathoadrenal lineage in avian embryos. II. Effects of glucocorticoids on cultured neural crest cells.

The neural crest-derived precursors of the sympathoadrenal lineage depend on environmental cues to differentiate as sympathetic neurons and pheochromocytes. We have used the monoclonal antibody A2B5 as a marker for neuronal differentiation and antisera against catecholamine synthesis enzymes to investigate the differentiation of catecholaminergic cells in cultures of quail neural crest cells. Cells corresponding phenotypically to sympathetic neurons and pheochromocytes can be identified in neural crest cell cultures after 5-6 days in vitro. Expression of the A2B5 antigen precedes expression of immunocytochemically detectable levels of tyrosine hydroxylase in cultured neural crest cells. Glucocorticoid treatment decreases the proportion of TH+ neural crest cells that express neuronal traits. We conclude that environmental cues normally encountered by sympathoadrenal precursors in vivo can influence the differentiation of a subpopulation of cultured neural crest cells in the sympathoadrenal lineage.

Adrenal Glands↗
PubMed2004

Early requirement of the transcriptional activator Sox9 for neural crest specification in Xenopus.

The neural crest is a multipotent population of cells that arises at the neural plate border in the vertebrate embryo. We have previously shown that a member of the Sox family of transcription factors, Sox9, is a regulator of neural crest formation in Xenopus, as Sox9-depleted embryos failed to form neural crest progenitors. Here, we describe experiments that further investigate Sox9 function during neural crest development. Induction of neural crest progenitors in Xenopus is regulated by Wnt signaling. We show that this process is largely dependent on Sox9 function as Wnt-mediated neural crest induction is inhibited in the context of Sox9-depleted embryos. Moreover, we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation. Expression of a construct in which Sox9 DNA-binding domain (HMG box) is fused to the repressor domain of Drosophila engrailed blocked neural crest formation, thereby mimicking the phenotype of Sox9-depleted embryos. Finally, using a hormone-inducible inhibitory mutant of Sox9, lacking the transactivation domain, we show that Sox9 function is required for neural crest specification but not for its subsequent migration.

Animals↗
PubMed1998

Paraxial-fated mesoderm is required for neural crest induction in Xenopus embryos.

Neural crest induction is thought to occur by a two-step process. Axially fated mesoderm induces neural plate, which is then recruited to neural crest by nonneural epidermal ectoderm at the neural plate border. This model suggests a rather indirect role for mesoderm in inducing neural crest. We extensively examined the role of mesoderm in neural crest induction by determining which types of mesoderm induce neural crest cells in Xenopus embryos. We found that noggin-dorsalized ventral marginal zone (VMZ) explants differentiate as melanocytes in the absence of axial mesoderm. Dorsalized VMZ is also a potent inducer of melanocytes when juxtaposed to animal cap ectoderm in recombinant explants. Dorsalized VMZ is analogous to the dorsal-lateral marginal zone (DLMZ) region of the embryo. Neural crest-inducing activities of gastrula stage DLMZ and dorsal marginal zone (DMZ) were also compared in recombinant explants. DLMZ was a stronger inducer of neural crest than was DMZ; DLMZ induced high levels of XSlug expression and melanocyte formation in recombinants, whereas DMZ weakly induced neural crest. In whole embryos lacking DLMZ, XSlug expression and melanocyte formation were significantly reduced; in contrast, no significant reduction of XSlug expression or melanocyte formation was seen in embryos lacking a DMZ. These results suggest that paraxial-fated mesoderm plays a central role in neural crest formation by inducing a novel type of lateral neural plate. This lateral neural plate is then recruited to neural crest by adjacent nonneural epidermal ectoderm.

Animals↗
PubMed1999

Development of neural crest in Xenopus.

The neural crest is a unique cell population among embryonic cell types, displaying properties of both ectodermal and mesodermal lineages. Most of the recent studies examining the neural crest have been performed in avian embryos. Only in the first half of this century were amphibians extensively used. We first summarize this important older source of information, reviewing studies made since the turn of the century. Due to the increasingly detailed in cellular and molecular knowledge of the early development of Xenopus laevis, the remainder of the review focuses on this species. We describe the route of migration and fate of the neural crest and propose a new model of neural crest induction in which prospective cells are induced independently of the neural plate by a double gradient of a morphogen that patterns the entire ectoderm. This model is also discussed in a more general context in connection with the dorsoventral patterning of the neural tube. Finally, we discuss some ideas concerning neural crest evolution and propose a novel hypothesis about its phylogenetic origin.

Amphibians↗
PubMed1990

Spatial and temporal distribution of vinculin and talin in migrating avian neural crest cells and their derivatives.

Neural crest cells express different adhesion modes at each phase of their development starting with their separation from the neural tube, followed by migration along definite pathways throughout the embryo, and finally to settlement and differentiation in elected embryonic regions. In order to determine possible changes in the cytoskeleton organization and function during these processes, we have studied the in situ distribution of two major cytoskeleton-associated elements involved in the membrane anchorage of actin microfilaments, i.e. vinculin and talin, during the ontogeny of the neural crest and its derivatives in the avian embryo. Prior to emigration, neural crest cells exhibited both vinculin and talin at levels similar to the neighbouring neural epithelial cells, and this expression apparently did not change as cells became endowed with migratory properties. However, vinculin became selectively enhanced in neural crest cells as they further migrated towards their final destination. This increase in vinculin amount was particularly striking in vagal and truncal neural crest cells entering cellular environments, such as the sclerotome and the gut mesenchyme. Talin was also expressed by neural crest cells but, in contrast to vinculin, staining was not conspicuous compared to neighbouring mesenchymal cells. High levels of vinculin persisted throughout embryogenesis in almost all neural derivatives of the neural crest, including the autonomous and sensory ganglia and Schwann cells along the peripheral nerves. In contrast, the non-neural derivatives of the neural crest rapidly lost their prominent vinculin staining after migration. The pattern of talin in the progeny of the neural crest was complex and varied with the cell types: for example, some cranial sensory ganglia expressed high amounts of the molecule whereas autonomic ganglia were nearly devoid of it. Our results suggest that (i) vinculin and talin may follow independent regulatory patterns within the same cell population, (ii) the level of expression of vinculin and talin in neural crest cells may be consistent with the rapid, constant modulations of their adhesive properties, and (iii) the expression patterns of the two molecules may also be correlated with the genesis of the peripheral nervous system.

Animals↗
PubMed2003

Gonadotropin-releasing hormone (GnRH) cells arise from cranial neural crest and adenohypophyseal regions of the neural plate in the zebrafish, Danio rerio.

The olfactory placodes generate the primary sensory neurons of the olfactory sensory system. Additionally, the olfactory placodes have been proposed to generate a class of neuroendocrine cells containing gonadotropin-releasing hormone (GnRH). GnRH is a multifunctional decapeptide essential for the development of secondary sex characteristics in vertebrates as well as a neuromodulator within the central nervous system. Here, we show that endocrine and neuromodulatory GnRH cells arise from two separate, nonolfactory regions in the developing neural plate. Specifically, the neuromodulatory GnRH cells of the terminal nerve arise from the cranial neural crest, and the endocrine GnRH cells of the hypothalamus arise from the adenohypophyseal region of the developing anterior neural plate. Our findings are consistent with cell types generated by the adenohypophysis, a source of endocrine tissue in vertebrate animals, and by neural crest, a source of cells contributing to the cranial nerves. The adenohypophysis arises from a region of the anterior neural plate flanked by the olfactory placode fields at early stages of development, and premigratory cranial neural crest lies adjacent to the caudal edge of the olfactory placode domain [Development 127 (2000), 3645]. Thus, the GnRH cells arise from tissue closely associated with the developing olfactory placode, and their different developmental origins reflect their different functional roles in the adult animal.

Animals↗
PubMed2000

Avian transitin expression mirrors glial cell fate restrictions during neural crest development.

During development, trunk neural crest cells give rise to three primary classes of derivatives: glial cells, melanocytes, and neurons. As part of an effort to learn how neural crest diversification is regulated, we have produced monoclonal antibodies (MAbs) that recognize antigens expressed by neural crest cells early in development. One of these, MAb 7B3 (7B3), was found to recognize an avian transitin-like protein by co-immunostaining with a series of transitin-specific monoclonal antibodies and by Western blot analysis. In neural crest cell cultures, we found that 7B3 initially recognizes the majority of neural crest cells as they emerge from the neural tube. Subsequently, 7B3-immunoreactivity (IR) is progressively restricted to a smaller subpopulation of cells. In fully differentiated trunk neural crest cell cultures, 7B3-IR is expressed only by cells that do not express neuronal markers and lack melanin granules. During development in vivo, 7B3-IR is evident in neural crest cells on the medial, but not the lateral migration pathway, suggesting that it is not expressed by melanocyte precursors. Later, the antigen is detected in non-neuronal, presumptive glial cells in dorsal root ganglia (DRG) and sympathetic ganglia, as well as along ventral roots. Cultures of E5 DRG confirm that 7B3-IR is restricted to non-neuronal cells of ganglia, many of which closely associate with neuronal processes. Therefore, of the three major classes of differentiated trunk neural crest derivatives, 7B3 exclusively recognizes glial cells, including both satellite glia and Schwann cells. Since the pattern of 7B3 expression in vitro mirrors the pattern of glial cell fate-restrictions in the trunk neural crest lineage, and is expressed by neural crest-derived glia in vivo, we conclude that 7B3 is an early pan-glial marker for neural crest-derived glial cells and their precursors.

Animals↗
PubMed2001

The early steps of neural crest development.

The neural crest is an intriguing cell population that gives rise to many derivatives which are all generated far from their final destinations. From its induction to the delamination of the cells, multiple signalling pathways converge to regulate the expression of effector genes, the products of which endow the cells with invasive and migratory properties reminiscent of those displayed by malignant cells in tumours. As such, the neural crest constitutes an excellent model to study cell migration.

Animals↗
PubMed1985

Small intensely fluorescent cells in culture: role of glucocorticoids and growth factors in their development and interconversions with other neural crest derivatives.

The neural crest gives rise to a number of adrenergic derivatives, including sympathetic neurons and adrenal chromaffin cells, which contain catecholamines (CAs) but differ in other morphological and functional characteristics. Small intensely fluorescent (SIF) cells, which exist primarily as a minority cell population in autonomic ganglia, are a third cell type in the sympathoadrenal branch of the neural crest lineage. In some respects these cells appear intermediate in phenotype between sympathetic neurons and adrenal chromaffin cells. We established pure dissociated cell cultures of SIF cells from rat superior cervical ganglia (SCG) and used these to study the role of environmental factors in SIF cell development and the relationship of these cells to the other cell types of the sympathoadrenal lineage. When cells from neonatal rat SCG were grown for 3 weeks in the presence of glucocorticoid and in the absence of nerve growth factor (NGF), pure cultures of SIF cells developed. The properties of the cells included (i) small cell size and the occasional presence of short neurites, (ii) intense CA histofluorescence and immunoreactivity for CA synthetic enzymes, (iii) synthesis and storage of CA from radioactive precursors, and (iv) characteristic ultrastructure. The concentration of the glucocorticoid and the presence or absence of non-neuronal cell factors influenced which types of SIF cells developed. In micromolar glucocorticoid most of the cells resembled adrenal chromaffin or type II SIF cells: they displayed immunohistochemically detectable phenylethanolamine-N-methyltransferase (PNMT), synthesized and stored epinephrine, and contained large granular vesicles (100 to 300 nm). When SCG cells were grown in 10(-8) M hormone, many fewer SIF cells developed and a higher percentage of these lacked PNMT immunoreactivity, had neurites, and contained vesicles of smaller mean diameter (70 to 130 nm), similar to those of type I SIF cells in vivo. In the presence of conditioned medium (medium conditioned by non-neuronal cells) as well as glucocorticoid, virtually all of the cells morphologically resembled type I SIF cells. In the absence of glucocorticoid, no SIF cells were ever observed after 3 weeks in culture. By following the development of CA histofluorescence and SIF cell ultrastructure in the cultures over time, we demonstrated that SIF cells were not present in large numbers in these cultures immediately after plating, but were induced from an apparently undifferentiated precursor by the hormonal environment, whereas most of the principal neurons died.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Cell death in cranial neural crest development.

The rhombencephalic neural crest, crucial to the patterning and development of many craniofacial structures, migrates laterally from the dorsal hindbrain, but not as a continuous sheet. We have used a vital dye to demonstrate a discontinuous pattern of cell death in the dorsal midline of the avian rhombencephalon associated with the migration of the neural crest. Whilst cell death commences in the dorsal midline of the presumptive mesencephalon at stage 8, two distinct domains of cell death are apparent in the rhombencephalon by stage 11. The rostral domain lies over primary rhombomere RhA1 and rhombomere rh3, while the caudal domain occurs on the neural midline between the otic vesicles, in the region of rh5. Using a marker for the neural crest, we show that the rostral and caudal domains of cell death correlate with the absence of neural crest migration from rh3 and rh5. Thus segment-specific cell death in the dorsal region of particular rhombomeres may account for their subsequent failure to contribute to the cranial neural crest.

Animals↗
PubMed2004

A slug, a fox, a pair of sox: transcriptional responses to neural crest inducing signals.

The neural crest, a cell type found only in vertebrate embryos, gives rise to the structures of the skull and face and most of the peripheral nervous system, as well as other cell types characteristic of vertebrates. These cells are of great clinical significance and a wide variety of congenital defects are due to aberrant neural crest development. Increasing numbers of studies are contributing to our understanding of how this group of cells form and differentiate during normal development. Wnt, FGF, BMP, and Notch-mediated signals all have essential roles in this process, and several of these signals appear to play multiple temporally distinct roles. Changes in the response of neural crest cells to the same signal over time may be mediated, in part, by an ever-changing cocktail of transcription factors expressed within these cells. Neural crest development is thus a complex multistep process, and elucidating the molecular mechanisms that mediate distinct aspects of this process will require that we determine the role of each of these factors alone and in combination. Here, we review some recent advances in our understanding of the signals and downstream transcription factors involved in neural crest cell formation.

Animals↗
PubMed1996

The genesis of avian neural crest cells: a classic embryonic induction.

Neural crest cells arise from the ectoderm and are first recognizable as discrete cells in the chicken embryo when they emerge from the neural tube. Despite the classical view that neural crest precursors are a distinct population lying between epidermis and neuroepithelium, our results demonstrate that they are not a segregated population. Cell lineage analyses have demonstrated that individual precursor cells within the neural folds can give rise to epidermal, neural crest, and neural tube derivatives. Interactions between the neural plate and epidermis can generate neural crest cells, since juxtaposition of these tissues at early stages results in the formation of neural crest cells at the interface. Inductive interactions between the epidermis and neural plate can also result in "dorsalization" of the neural plate, as assayed by the expression of the Wnt transcripts characteristic of the dorsal neural tube. The competence of the neural plate changes with time, however, such that interaction of early neural plate with epidermis generates only neural crest cells, whereas interaction of slightly older neural plate with epidermis generates neural crest cells and Wnt-expressing cells. At cranial levels, neuroepithelial cells can regulate to generate neural crest cells when the endogenous neural folds are removed, probably via interaction of the remaining neural tube with the epidermis. Taken together, these experiments demonstrate that: (i) progenitor cells in the neural folds are multipotent, having the ability to form multiple ectodermal derivatives, including epidermal, neural crest, and neural tube cells; (ii) the neural crest is an induced population that arises by interactions between the neural plate and the epidermis; and (iii) the competence of the neural plate to respond to inductive interactions changes as a function of embryonic age.

Animals↗
PubMed1993

Regulative capacity of the cranial neural tube to form neural crest.

In avian embryos, cranial neural crest cells emigrate from the dorsal midline of the neural tube shortly after neural tube closure. Previous lineage analyses suggest that the neural crest is not a pre-segregated population of cells within the neural tube; instead, a single progenitor in the dorsal neural tube can contribute to neurons in both the central and the peripheral nervous systems (Bronner-Fraser and Fraser, 1989 Neuron 3, 755-766). To explore the relationship between the 'premigratory' neural crest cells and the balance of the cells in the neural tube in the midbrain and hindbrain region, we have challenged the fate of these populations by ablating the neural crest either alone or in combination with the adjoining ventral portions of the neural tube. Focal injections of the vital dye, DiI, into the neural tissue bordering the ablated region demonstrate that cells at the same axial level, in the lateral and ventral neural tube, regulate to reconstitute a population of neural crest cells. These cells emigrate from the neural tube, migrate along normal pathways according to their axial level of origin and appear to give rise to a normal range of derivatives. This regulation following ablation suggests that neural tube cells normally destined to form CNS derivatives can adjust their prospective fates to form PNS and other neural crest derivatives until 4.5-6 hours after the time of normal onset of emigration from the neural tube.

Animals↗